2-Substituted -1,2,4-thiadiazolo-(2,3-a)benzimidazoles and process for their preparation

ABSTRACT

Novel 2-substituted-1,2,4-thiadiazolo-(2,3-a)-benzimidazoles of the formula   AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF; AND PROCESS FOR THEIR PREPARATION. These 2-substituted-1,2,4-thiadiazolo(2,3-a)-benzimidazoles are useful as fungistatic and fungicidal agents.

Uiiited States Patent 1 Beard [451 Apr. 29, 1975 Z-SUBSTITUTED-1,2,4-THlADlAZOL0-(2,3- A)BENZIMIDAZOLES AND PROCESS FOR THEIRPREPARATION [75] Inventor: Colin C. Beard, Palo Alto, Calif.

[73] Assignee: Syntex (U.S.A.) Inc., Palo Alto,

Calif.

[22] Filed: Oct. 4, 1973 [21] Appl. No.: 403,474

[52] US. Cl. ..260/306.8 F; 260/250 BN; 260/256.5 R;

424/263; 424/270 [51] Int. Cl C07d 99/10 OTHER PUBLICATIONS Chekril etal., Chem. Abstracts, 7818431 ly (1973).

Primary Examiner-Richard J. Gallagher Attorney, Agent, or FirmGerard A.Blaufarb; Leon Simon; William B. Walker [57] ABSTRACT Novel I2-substituted-1,2,4-thiadiazol0-[2,3-a]- benzimidazoles of the formulaand the pharmaceutically acceptable salts thereof; and process for theirpreparation. These 2-substitutedl,2,4-thiadiazolo-[2,3-al-benzimidazolesare useful as fungistatic and fungicidal agents.

15 Claims, N0 Drawings Z-SUBSTITUTED-1,2,4-THIADIAZOLQ-(2,3-A)BENZIMIDAZOI:,ES AND PROCESS FOR THEIRPREPARATION This invention relates to novel 2-substituted-l,2.4-thiadiazolo-[2,3-a]-benzimidazole compounds of the formula:

wherein R is 1R3 I N r F ii- N I I R is hydrogen or lower alkyl; and thepharmaceutically acceptable salts thereof, and processes for thepreparation thereof.

The terms lower alkoxy, lower alkyl, lower alkylthio, and loweralkylsulfinyl as used above and in the claims are inclusive of moietiescontaining from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl,isopropyl, butyl and tert.-butyl.

The term -halo" as used above and in the claims is inclusive of chloro,bromo, fluoro and iodo.

The compounds of Formula I are chemotherapeutic agents which possessfungistatic and fungicidal properties and thus are useful in combattingfungus infections.

Amonst the Amongst against which the compounds of Formula I exhibitfungistatic and fungicidal activity are:

M. amlounini H. gramineum E. floccuxmn M. gypsum T. mmlagrophymv Mr(unis C. alhicans T. ruhrum Cr. "('OfiIIIlMIIS T. wnsuram" R. .rulani T..l'('hllt'llf('illii A. .voluni Particularly preferred are thosecompounds of Formula I wherein R is phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-methylthiophenyl,4-methylsulfinylphenyl, 4-tert.-butylphenyl, 4-trifluoromethylphenyl,2-furyl, 3-furyl, Z-naphthyl, 2- thienyl, 3-thienyl, Z-thiazolyl,4-thiazolyl, S-thiazolyl, 2-methyl-4-thiazolyl, Z-pyridyl, 3-pyridyl,4-pyridyl. 2- pyrazinyl, 3-isothiazolyl, 4-isothiazolyl. S-isothiazolyl.l,2,3-thiadiazolyl, and 1,2.5-thiadiazolyl.

The compounds of Formula I are prepared according to the followinggeneralized reaction scheme:

The Z-substituted l,2,4-thiadiazolo-[ 2,3-a benzimidazole compounds ofFormula I are obtained by treating the compounds of Formula IV with anoxidizing agent, e.g., m-chloroperbenzoic acid, bromine, chlorine,sulfuryl chloride, peracetic acid, hydrogen peroxide, and the like, at atemperature of from about 40 to 40C., for from about one-fourth to 6hours, in an inert organic solvent, e.g., chloroform, and the like. Whenthe reaction is carried out using bromine or chlorine it is preferredthat the temperature be between about and 30C. In addition, when theoxidation rewherein R is defined as above.

The carbonylamino compounds of Formula III are obtained by treating the2-aminobenzimidazole of Formula II with an acid chloride (RCOCI), acidester (RCOOR wherein R is methyl or ethyl), or the mixed anhydride of afree acid (RCOOH) and trifluoroacetic acid.

The reaction of the compounds of Formula II with an acid chloride(RCOCl) to obtain the carbonylamino compounds of Formula III is carriedout in the presence of an organic solvent, e.g., pyridine, acetone,tetrahydrofuran, and the like, at a temperature of from about 40 to 35C.for from about 2 to hours.

The reaction of the compound of Formula II with an acid ester (RCOOR toobtain the carbonylamino compounds of Formula [II is carried out at atemperature of from about 100 to 200C. for from about I to 20 hours.

The reaction of the compound of Formula II with a mixed anhydride of afree acid (RCOOH) and trifluoroacetic acid, prepared from the free acidand trifluoroacetic acid anhydride, to obtain the carbonylaminocompounds of Formula I" is carried out in the presence of an inertorganic solvent, e.g., tetrahydrofuran, acetone, and the like, and inthe presence of a base, e.g., triethylamine, and the like, at atemperature of from about 20 to C. for from about 1 to 20 hours.

The thus-obtained carbonylamino compounds of Formula III, obtained byreaction with an acid chloride, acid ester, or mixed anhydride, asdescribed above, are then converted to the correspondingthionylcarbonylamino compounds of Formula IV by treatment withphosphorous pentasulfide (P 8 in an inert organic solvent, e.g.,pyridine, dioxane, and the like, at a temperature of from about 80 to120C, for from about I to 20 hours.

action is carried out using bromine or chlorine, the compounds ofFormula l can, if desired, be isolated as their pharmaceuticallyacceptable hydrobromide or hydrochloride salts, or treated with a base,e.g., ammonia, sodium or potassium bicarbonate and the like, to obtainthe corresponding free bases.

When the oxidation reaction is carried out using other than bromine orchlorine, the thus-obtained free bases of Formula I can be converted totheir pharmaceutically acceptable salts by reaction withpharmaceutically acceptable acids, for example, inorganic acids, e.g.,halogen hydroacids (particularly hydrochloric and hydrobromic), nitricacid, phosphoric acids, sulphonic acids, monoand dicarboxylic acids, andthe like; and organic acids, e.g., acetic, maleic, succinic, tartaric,lactic, citric, sorbic, salicylic, and the like.

Alternatively, the 2-(methylsulfinylphenyl)-I,2,4-thiadiazolo[2,3-a]-benzimidazole compounds of Formula I are obtained bysubjecting the corresponding 2- (methylthiophenyl )-l ,2,4-thiadiazolo-[2,3-a]- benzimidazole compounds to a further oxidation with an oxidizingagent, e.g., m-chloroperbenzoic acids, peracetic acid, and the like, inthe presence of an inert organic solvent, e.g., chloroform,dichloromethane, and the like, at temperatures of from about 30 to 30C.for from one-half to 24 hours.

The thus-obtained 2-(methylsulfinylphenyl)-l,2,4-thiadiazolo-[2,3-a]-benzimidazole compounds can then be converted totheir pharmaceutically acceptable salts as previously described.

The compounds of Formula I, or the pharmaceutically acceptable saltsthereof, can be formulated into solutions, creams and ointments,according to methods known to those skilled in the art, for topicaladministration. Preferably a concentration of from about 0.5 to 5percent of the active ingredient is used.

It is to be understood that isolation of the compounds described hereincan be effected by any suitable sepa-. ration or purification procedure,such as, for example, extraction, filtration, evaporation, distillation,crystallization, thin-layer chromatography or column chromatography, ora combination of these procedures lllustrations of suitable separationand isolation procedures can be had by reference to the examplesdescribed herein below. However, other equivalent separation orisolation procedures could, of course, also be used.

A further understanding of the invention can be had from the followingnon-limiting examples. Also, where necessary, examples are repeated toprovide starting materials for subsequent examples.

EXAMPLE 1 A. A solution of 20 g. of Z-aminobenzimidazole (ll) in 150 ml.of pyridine is cooled to 20C. and 20 g. of 3-furoyl chloride is addedthereto. The thus-obtained reaction mixture is allowed to warm slowly tobetween 20 and 30C. (room temperature), and maintained at thistemperature for hours, diluted with water and filtered to give a residuewhich is recrystallized from acetic acid to yield2-(3-furylcarbonylamino)- benzimidazole [(lll), R 3-furyl].

Similarly, substituting a stoichiometric equivalent amount of benzoylchloride,

4-chlor0benzoyl cloride,

4-methoxybenzoyl chloride,

4-methylbenzoyl chloride,

4-methylthiobenzoyl chloride,

4-methylsulfinylbenzoyl chloride,

4-tert.-butylbenzoyl chloride, 4-trifluoromethylbenzoyl chloride,

2 furoyl chloride,

Z-naphthoyl chloride,

2-thenoyl chloride,

3-thenoyl chloride,

4-thiazoloyl chloride,

S-thiazoloyl chloride,

2-methyl-4-thiazoloyl chloride,

1,2,3-thiadiazol-4-oyl chloride, and

1,2,5-thiadiazol-3-oyl chloride, for 3-furoyl chloride in the procedureof Example 1A is productive of 2-phenylcarbonylamino-benzimidazole2-(4-chlorophenylcarbonylamino)-benzimidazole2-(4-methoxyphenylcarbonylamino)-benzimidazole,2-(4-methylphenylcarbonylamino)-benzimidazole,2-(4-methylthiophenylcarbonylamino)- benzimidazole,2-(4-methylsulfinylphenylcarbonylamino)- benzimidazole,2-(4-tert.-butylphenylcarbonylamino)- benzimidazole,2-(4-trifluoromethylphenylcarbonylamino)- benzimidazole,2-(2-furylcarbonylamino)-benzimidazole,2-(Z-naphthylcarbonylamino)-benzimidazole,

2-( Z-thienylcarbonylamino)-benzimidazole,

2-(3-thienylcarbonylamino)-benzimidazole,

2-(4-thiazolylcarbonylamino)-benzimidazole,

2-(S-thiazolylcarbonylamino)-benzimidazole,

2-(2-methyl-4-thiazolylcarbonylamino)- benzimidazole, I

2-( l,2,3-thiadiazol-4-ylcarbonylamino benzimidazole, and

2-( l,2,5-thiadiazol-3-ylcarbonylamino)- benzimidazole, respectively.

B. A mixture of 9 g. of Z-aminobenzimidazole (ll) and 10 g. of3-pyridinecarboxylic acid methyl ester (methyl nicotinate) is heated atl60C. for about 10 hours. The reaction mixture is then triturated with50 ml. of hot methanol, followed by filtration to yield a residuecomprising 2-(3-pyridylcarbonylamino)- benzimidazole [(lll), R3-pyridyl].

Similarly, substituting a stoichiometric equivalent amount of2-thiazolecarboxylic acid methyl ester,

Z-pyridinecarboxylic acid methyl ester, and

4-pyridinecarboxylic acid methyl ester for 3 pyridinecarboxylic acidmethyl ester in the procedure of Example 1B is productive of2-(2-thiazolylcarbonylamino)-benzimidazole,

2-(Z-pyridylcarbonylamino)-benzimidazole, and

2-(4-pyridylcarbonylamino)-benzimidazole, respectively.

C. 3.7 G. of 2-pyrazinecarboxylic acid is suspended in 20 ml. of drytetrahydrofuran and 6.3 g. of trifluoroacetic anhydride is addedthereto. To the resulting solution, at 20-25C., there is added 8.5 ml.of triethylamine and 4 g. of 2-aminobenzimidazole (ll) and thethus-obtained reaction mixture is stirred at 20-25C. for about 5 hours.200 Ml. of water is then added, followed by filtration and the residueis recrystallized from aqueous acetic acid to yield2-(2-pyrazinylcarbonylamino)-benzimidazole [(III), R 2-pyrazinyl].

Similarly, substituting a stoichiometric equivalent amount of3-isothiazolecarboxylic acid,

4-isothiazolecarboxylic acid, and

5-isothiazolecarboxylic acid, for Z-pyrazinecarboxylic acid in theprocedure of Example IC is productive of2-(3-isothiazolylcarbonylamino)-benzimidazole,

2-(4-isothiazolylcarbonylamino)-benzimidazole, and

2-(5-isothiazolylcarbonylamino)-benzimidazole, respectively.

EXAMPLE 2 To l0 g. of 2-(3-furylcarbonylamino)-benzimidazole [(III), R3-furyl] in 200 ml. of pyridine is added 10 g. of phosphorouspentasulfide and the reaction mixture is heated to l00-l 10C. for 10hours. The bulk of the pyridine is removed under vacuum and the residueis treated with 500 ml. of saturated potassium bicarbonate solution,filtered and recrystallized from methanol-chloroform to yield 2-(3-furylthiocarbonylamino)-benzimidazole [(lV), R 3-furyl].

Similarly, substituting a stoichiometric equivalent amount of the othercompounds obtained in Example 1A; the compounds obtained in Example 1B;and the compounds obtained in Example 1C; for2-(3-furylcarbonylamino)-benzimidazole, and following the procedure ofExample 2 is productive of 2-phenylthiocarbonylamino-benzimidazole,

2-(4-chlorophenylthiocarbonylamino)- benzimidazole,

2-(4-methoxyphenylthiocarbonylamino)- benzimidazole,

2-(4-methylphenylthiocarbonylamino)- benzimidazole,

2-(4-methylthiophenylthiocarbonylamino)- benzimidazole,

Similarly, substituting a stoichiometric equivalent R amount of 2-(2-pyridylthiocarbonylamino S benzimidazole for2-(2-pyrazinylthiocarbonylamino)- N/ I benzimidazole in the procedure ofExample 3B is productive of 2-(2-pyridyl)-l,2,4-thiadiazolo-[2,3-a]-benzimidazole. N

C. To 0.28 g. 2-(4-methylthiophenyl)-l,2,4-

thiadiazolo-benzimidazole [(l), R 4- I methylthiophenyl] in 250 ml. ofchloroform and 5 ml.

of methanol at 20C. is added 0.2 g. of mchloroperbenzoic acid in ml. ofchloroform. The rewherein R is and action mixture is allowed to stand at2025C. for 5 in which R and R are hydrogen, lower alkoxy, halo,

hours, washed with 20 ml. of dilute sodium bicarbonate nitro, loweralkyl, lower alkylthio, lower alkylsulfisolution, 20 ml. of water anddried over magnesium sulnyl, or trifluoromethyl;

fate, The chloroform solution is concentrated and the R is hydrogen,lower alkoxy, halo, nitro, or lower alresidue remaining isrecrystallized from methanolkyl;

chloroform to yield 2-(4-methylsulfinylphenyl)-l,2,4- and thepharmaceutically acceptable salts thereof.

thiadiazolo-[2,3-al-benzimidazole. 2. A compound of claim 1 wherein R isphenyl, 4-

In the Examples above, specific reaction sequences p y yp y y p y havebeen extended, in a general sense, to the preparamethylthiophenyh y p y44cm tion of other similar and related compounds. It should y p y f y ly 'y Y be understood, however, that with respect to any comp yL2411181134 and y pound which has been prepared by the extension of a Thecompound of Claim 2 wherein R is P y specific reaction sequence, it maybe necessary or dey 'l sirable to utilize solvents, reaction media.recrystalli- The compound of Claim 2 wherein R is zation media, reactiontimes or temperatures, etc.. chlorophenyl, 'P y other than the onesgiven in the specific reaction se- 45 quence upon which such extensionis based. Addition- The compound of Claim 2 wherein R is ally, thespecific reaction sequence or manner in which yp y yp yh- 1 2.

particular compounds are to be prepared will depend,thifldiaZOlO-ll3-al-benlimidaloleinter alia, upon the availability ofthe necessary starting 6. The compound of claim 2 wherein R is 4-materials, or the ease in which the desired starting mamethylphenyl,2-(4-methylphenyl)-l,2,4-thiadiazoloterials can be prepared, and thereactivity thereof. [2,3-a1-benzimidazole.

These variations are deemed to be within the skill of 7. The compound ofclaim 2 wherein R is 4- those working in this art and will be apparentfrom a methylthiophenyl, 2-(4-methylthiophenyl)-l,2,4-

consideration of the particular reactants utilized and/or thiadiazolo-[2,3-a]-benzimidazole.

particular compound desired to be produced. 8. The compound of claim 2wherein R is 4-methyl- While the present invention has been describedwith ulfinylphenyl, 2-(4-methylsulfinylphenyl)-l,2,4-

reference to specific embodiments thereof, it should bethifldia20l0-l23-a]-benZimidaZ0l6- understood by those skilled in thisart that various 9. The compound of claim 2 wherein R is 4-tert.-

changes may be made and equivalents may be substibutylphenyl,2-(4-tert.-butylphenyl)-l,2,4-thiadiazolotuted without departing fromthe true spirit and scope [2,3-a]-benzimidazole.

of the invention. In addition. many modifications may 10. The compoundof claim 2 wherein R is 4-tribe made to adapt a particular situation,material or fluoromethylphenyl, 2-(4-trifluoromethylphenyl)- compositionof matter, process, process step or steps,l,2,4-thiadiazolo-[2,3-a]-benzimidazole.

or then-present objective to the spirit of this invention 11. Thecompound of claim 2 wherein R is 2-furyl,

without departing from its essential teachings.2-(2-furyl)-l,2,4-thiadiazolo-[2,3-a]-benzimidazole.

What is claimed is: 12. The compound of claim 2 wherein R is 3-furyl,

l. A compound represented by the formula 2-(3-furyl)-l,2,4-thiadiazolo-[2,3-a]-benzimidazole.

13. The compound of claim 2 wherein R is 2- 2-(2-thienyl)-l,2,4-thiudiazolo-[2.3-a]-benzimidazole. naphthyl, 2-(2-naphthyl)-l,24-thiadiazolo-[2,3-a]- 15. The compound of claim 2 wherein R is3-thienyl benzimidazolei 2-( 3-thienyl)- l ,2 4-thiadiazolo-[2,3-al-benzimidazole.

14. The compound of claim 2 wherein R is 2-thienyl,

UNITED STATES PATENT OFFICE W C R c T (:0 c ION Patent No. 3'880'874Dated Ap il 29, 1975 Inventor) Col1n C. Beard It is certified that errorappears in the aboveidentified patent and that said Letters Patent arehereby corrected as shown below:

Column 2, line 17, Amonst should read Amongst and "Amongst" should readfungi Column 5, line 29, "cloride" should read chloride Column 7, line33, "furly" should read furyl Column 10, Claim 1, line 0 30, "arehydrogen" should read are each hydrogen Signed and Scaled this eleve th3 0 [SEAL] D y f May 1976 Arrest:

RUTH. C. M:ASON C. MARSHALL DANN I Q 1 (mnmissimu'r ()fl'algnfs jTrademark-X

2. A compound of claim 1 wherein R is phenyl, 4-chlorophenyl,4-methoxyphenyl, 4-methylphenyl, 4-methylthiophenyl,4-methylsulfinylphenyl, 4-tert.-butylphenyl, 4-trifluoromethylphenyl,2-furyl, 3-furyl, 2-naphthyl, 2-thienyl, and 3-thienyl.
 3. The compoundof claim 2 wherein R is phenyl,2-phenyl-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 4. The compound ofclaim 2 wherein R is 4-chlorophenyl,2-(4-chlorophenyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 5. Thecompound of claim 2 wherein R is 4-methoxyphenyl,2-(4-methoxyphenyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 6. Thecompound of claim 2 wherein R is 4-methylphenyl,2-(4-methylphenyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 7. Thecompound of claim 2 wherein R is 4-methylthiophenyl,2-(4-methylthiophenyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 8. Thecompound of claim 2 wherein R is 4-methylsulfinylphenyl,2-(4-methylsulfinylphenyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole. 9.The compound of claim 2 wherein R is 4-tert.-butylphenyl,2-(4-tert.-butylphenyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 10. Thecompound of claim 2 wherein R is 4-trifluoromethylphenyl,2-(4-trifluoromethylphenyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole. 11.The compound of claim 2 wherein R is 2-furyl, 2-(2-furyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 12. The compound of claim 2wherein R is 3-furyl, 2-(3-furyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 13. The compound of claim 2wherein R is 2-naphthyl,2-(2-naphthyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 14. The compoundof claim 2 wherein R is 2-thienyl,2-(2-thienyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.
 15. The compoundof claim 2 wherein R is 3-thienyl,2-(3-thienyl)-1,2,4-thiadiazolo-(2,3-a)-benzimidazole.